We believe that if the mechanisms underlying stem cell activity in development and normal secretory cell turnover in mouse submandibular gland can be understood, then ultimately a bio-therapy for treatment of salivary gland dysfunction may be developed. Stem cells in the intercalated ducts of the submandibular gland have the potential to give rise to the two main secretory cell types of the mature gland: acinar cells and granular duct cells. The mechanisms maintaining and regulating stem cell function within the constraints of the basic tubular structure of salivary gland parenchyma are not known. We hypothesize that the stem cells ar held at the developmental stage, protodifferentiation, and that epidermal growth factor (EGF) is instrumental in regulating their course. Furthermore, we believe that the gender-related difference in circulating levels of EGF influences stem cell productivity sufficiently to be partially responsible for the overt gender dimorphism seen in the adult gland. We also suggest that the loss of mature secretory parenchyma nd accumulation of putative intermediate cells with aging represents an interruption in stem cell function that is linked with the age-related decline in EGF levels. The protodifferentiated stage is characterized by the presence of low levels of cell type-specific secretory protein and its homologous mRNA in cytologically undifferentiated cells. Thus the strategy for validating the protodifferentiated nature of stem cell sin the neonatal submandibular gland is to show that intercalated duct cells destined to give rise to granular duct cells at puberty, individually contain the species of nerve growth factor (NGF) and its transcript indicative of the granular duct cell phenotype. For stem cells which continue into adulthood, we intend to show that these stem cells individually contain low levels of both acinar cell and granular duct cell-specific polypeptides, mucin and NGF respectively. The role of EGF will be evaluated from patterns of proliferation and differentiation of progeny of the stem cells by continuously infusing EGF into adult females and castrate adult males. Finally, we intend to show that the overall decline with aging in secretory parenchyma is not due to a lack of stem cell proliferation and differentiation of stem cells and their progeny will be compared in mature and senescent adults. Reversal of the age- related changes in stem cell productivity by EGF supplementation will provide evidence for its involvement.